Development and application of new imaging technologies for the discovery of biomarkers of inflammatory arthritic disease onset, progression, and response to therapy are of broad interest and are common goals of physicians, medical researchers and scientific entities such as the NIH. Presenting high resolution optical information in soft tissues with imaging depth up to several centimeters, innovative spectroscopic photoacoustic tomography (SPAT) offers significant benefits to the diagnosis and treatment of inflammatory arthritis, particularly in combination with more established ultrasound imaging (US). SPAT, in addition to capturing peripheral bone and soft tissue images, has the unique capability to quantify tissue hemodynamic properties including regional blood oxygenation and blood volume, both abnormal in synovial tissue associated with inflammatory arthritis. Therefore, findings from SPAT should lead to creation of new direct and sensitive tissue-specific biomarkers, and may have revolutionary impact on clinical management of arthritis. Based on our past validation in animals and human cadaver joints, this physiological imaging modality will be adapted to human inflammatory arthritis for the first time in the proposed research. Through collaboration with the NIH Ultrasonic Transducer Resource Center, we will develop a specially designed SPAT and US dual-modality system employing the state-of-the-art ultrasonic imaging and transducer development technologies. This system will enable simultaneous SPAT and US imaging of human peripheral joints in real-time. Moreover, it can present physicians with both optical and ultrasonic contrast as well as tissue physiological information. Through the experiments on normal volunteers and rheumatoid arthritis patients, we will examine the performance of SPAT and US in imaging the articular tissue structures of peripheral joints and their ability in visualizing morphological biomarkers of rheumatoid arthritis. More interestingly, we will explore the potential of SPAT in assessing new physiological biomarkers of synovitis including hyperemia and hypoxia. We expect that, with sensitivity and specificity comparable to MRI but without using a contrast agent, this cost-effective imaging may provide unique opportunities for arthritis, including pre-diagnosis, identification of initial natural disease sequelae and progression, along with monitoring of non-pharmaceutical and pharmaceutical based interventions.